Efficient synthesis of highly substituted thiophenes from acetylenic esters, ethyl bromopyruvate, and tetramethylthiourea

Article abstract of DOI:10.1007/s00706-008-0918-0

The reaction of acetylenic esters with ethyl bromopyruvate in the presence of tetramethylthiourea led to highly functionalized thiophenes in excellent yields.

Full text of DOI:10.1007/s00706-008-0918-0

Monatsh Chem 139, 1257–1259 (2008)
DOI 10.1007/s00706-008-0918-0
Printed in The Netherlands
Efficient synthesis of highly substituted thiophenes from acetylenic esters,
ethyl bromopyruvate, and tetramethylthiourea
Issa Yavari, Zinatossadat Hossaini, Samereh Seyfi, Faezeh Shirgahi-Talari
Chemistry Department, Tarbiat Modares University, Tehran, Iran
Received 20 February 2008; Accepted 27 February 2008; Published online 15 May 2008
# Springer-Verlag 2008
Abstract The reaction of acetylenic esters with ethyl
bromopyruvate in the presence of tetramethylthiourea
led to highly functionalized thiophenes in excellent
yields.
Results and discussion
As part of our current studies on the development of
new routes in heterocyclic synthesis [12–16], we now
describe an efficient procedure for the direct synthesis
of highly substituted thiophenes from the one-pot
reaction of electron-deficient acetylenic esters with
ethyl bromopyruvate in the presence of tetramethyl-
thiourea at room temperature (Scheme 1).
Keywords Ethyl bromopyruvate; Activated acetylenes;
Substituted thiophene; tetramethylthiourea.
Introduction
The structures of 4a–4e were deduced from their
1
elemental analyses and their IR, H, and 13C NMR
Thiophenes are an important class of heterocyclic
compounds. A variety of molecules containing the
thiophene ring system display biological activity
and find application as pharmaceuticals [1], fragrance
compounds [2], or pharmacophoric entities [3, 4].
Moreover, they are also useful synthesis interme-
diates, in the preparation of new conducting polymers
[5, 6] or nonlinear optical materials [7]. Substituted
thiophenes can be prepared by proper functionali-
zation of the thiophene ring, usually through ꢀ-meta-
lation or ꢁ-halogenation reactions [1]. However,
annulation reactions of suitably substituted acyclic
precursors represent an attractive alternative method-
ology, which may allow direct regioselective prepara-
tion of the target molecule. Recently, several new
methods have been developed which illustrate the
utility of the latter approach [8–11].
1
spectra. For example, the H NMR spectrum of 4a
exhibited three singlets for dimethylamino (ꢂ ¼
3.12 ppm) and methoxy (ꢂ ¼ 3.78 and 3.95 ppm) pro-
tons, together with characteristic multiplets for the
ethoxy group. In the 13C NMR spectrum, the signals
corresponding to ester and ketone carbonyl groups of
the major isomer of 4a were observed at ꢂ ¼ 161.9,
162.5, 167.5, and 173.2 ppm. The mass spectrum of
4a displayed the molecular ion peak at m=z ¼ 343.
Mechanistically, it is conceivable that the reaction
involves the initial formation of a 1,5-dipolar in-
termediate 5 between tetramethylthiourea and the
acetylenic compound, which reacts with ethyl bro-
mopyruvate to produce 6. Intermediate 6 is converted
to the 1,6-diionic compound 7 via elimination of HBr.
Cyclization of this intermediate leads to 8, which
is converted to 4 by elimination of dimethylamine
(Scheme 2).
In conclusion, the reaction of dialkyl acetylenedi-
carboxylates or alkyl propiolates with ethyl bromo-
pyruvate in the presence of tetramethylthiourea led
Correspondence: Issa Yavari, Chemistry Department,
Tarbiat Modares University, P.O. Box 14115-175, Tehran,
Iran. E-mail: yavarisa@modares.ac.ir

1258
I. Yavari et al.
Scheme 1
Scheme 2
10), 312 (65), 299 (64), 284 (42), 59 (84), 31 (100); 1H
to substituted thiophenes. The present procedure has
the advantage that the reaction is performed under
neutral conditions, and the starting material can be
used without any activation or modification.
NMR: ꢂ ¼ 1.35 (t, 3J ¼ 7.2 Hz, Me), 3.08 (s, NMe2), 3.78 (s,
OMe), 3.95 (s, OMe), 4.33 (q, 3J ¼ 7.2 Hz, OCH2) ppm; 13
C
NMR: ꢂ ¼ 13.9 (Me), 41.2 (NMe2), 51.8 (OMe), 52.6 (OMe),
62.6 (OCH2), 128.6 (C), 130.6 (C), 148.2 (C), 154.2
(C), 161.9 (C¼O), 162.5 (C¼O), 167.5 (C¼O), 173.2 (C¼O)
ppm.
Experimental
Diethyl 2-(dimethylamino)-3-(2-ethoxy-2-oxoacetyl)thio-
phene-4,5-dicarboxylate (4b, C16H21NO7S)
Compounds 1–3 were obtained from Fluka and were used
without further purification. Mp: Electrothermal-9100 ap-
paratus. IR Spectra: Shimadzu IR-460 spectrometer. H and
13C-NMR spectra: Bruker DRX-500 AVANCE instrument;
in CDCl3 at 500.1 and 125.7 MHz; ꢂ in ppm, J in Hz. EI-
MS (70 eV): Finnigan-MAT-8430 mass spectrometer, in m=z.
Elemental analyses (C, H, and N) were performed with a
Heraeus CHN-O-Rapid analyzer; their results agreed favor-
ably with the calculated values.
1
Yellow oil; yield: 0.58g (78%); IR (KBr): ꢃꢀ¼ 1716, 1654,
1474, 1429, 1369, 1304, 1231, 1105cmꢀ1; EI-MS: m=z
(%) ¼ 371 (Mþ, 15), 326 (75), 298 (56), 292 (62), 73 (82),
45 (100); 1H NMR: ꢂ ¼ 1.28 (t, 3J ¼ 7.2 Hz, Me), 1.34 (t,
3
3J ¼ 7.2 Hz, Me), 1.40 (t, J ¼ 7.2 Hz, Me), 3.04 (s, NMe2),
3
3
4.34 (q, J ¼ 7.2 Hz, OCH2), 4.38 (q, J ¼ 7.2 Hz, OCH2),
4.41 (q, 3J ¼ 7.2 Hz, OCH2) ppm; 13C NMR: ꢂ ¼ 13.9 (Me),
14.1 (Me), 14.3 (Me), 43.9 (NMe2), 61.5 (OCH2), 61.9
(OCH2), 62.4 (OCH2), 127.5 (C), 129.7 (C), 149.1 (C),
152.7 (C), 162.7 (C¼O), 163.4 (C¼O), 168.6 (C¼O), 175.4
(C¼O) ppm.
General procedure for the preparation of compounds 4
To a stirred solution of 2 mmol 1 and 0.39 g 2 (2mmol) in
15cm3 CH2Cl2 was added 0.26 g tetramethylthiourea (2mmol)
at rt. The reaction mixture was stirred for 12h. The solvent
was removed under reduced pressure, and the residue was
purified by column chromatography (SiO2; n-hexane:AcOEt
10:1) to afford pure 4.
Methyl 2-(dimethylamino)-3-(2-ethoxy-2-oxoacetyl)thio-
phene-4-carboxylate (4c, C12H15NO5S)
Yellow oil; yield: 0.42g (73%); IR (KBr): ꢃꢀ¼ 1725, 1696,
1627, 1574, 1469, 1399, 1226cmꢀ1; EI-MS: m=z (%) ¼
285 (Mþ, 5), 254 (55), 241 (64), 226 (76), 59 (84), 31
(100); 1H NMR: ꢂ ¼ 1.31 (t, 3J ¼ 7.2 Hz, Me), 3.01 (s,
Dimethyl 2-(dimethylamino)-3-(2-ethoxy-2-oxoacetyl)-
thiophene-4,5-dicarboxylate (4a, C14H17NO7S)
Yellow oil; yield: 0.62g (90%); IR (KBr): ꢃꢀ¼ 1721, 1636,
3
1529, 1453, 1366, 1254 cmꢀ1; EI-MS: m=z (%) ¼ 343 (Mþ,
NMe2), 3.76 (s, OMe), 4.38 (q, J ¼ 7.2 Hz, OCH2), 7.30 (s,

Efficient synthesis of highly substituted thiophenes
1259
CH) ppm; 13C NMR: ꢂ ¼ 13.9 (Me), 45.4 (NMe2), 51.8 (OMe),
62.3 (OCH2), 115.9 (C), 132.8 (CH), 136.3 (C), 155.0 (C),
163.2 (C¼O), 167.1 (C¼O), 179.1 (C¼O) ppm.
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Yellow oil; yield: 0.45g (75%); IR (KBr): ꢃꢀ¼ 1693, 1633,
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7.2 Hz, Me), 3.06 (s, NMe2), 4.22 (q, 3J ¼ 7.2Hz, OCH2), 4.29
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1
3
(85), 73 (80), 45 (100); H NMR: ꢂ ¼ 1.23 (t, J ¼ 7.2 Hz,
Me), 1.36 (t, 3J ¼ 7.2 Hz, Me), 3.12 (s, NMe2), 4.10 (q,
3J ¼ 7.2 Hz, OCH2), 4.26 (q, 3J ¼ 7.2 Hz, OCH2), 6.85
(t, 3J ¼ 8.2 Hz, 2CH), 7.42 (t, 3J ¼ 8.2 Hz, CH), 8.15 (d,
3J ¼ 8.2 Hz, 2CH) ppm; 13C NMR: ꢂ ¼ 13.8 (Me), 14.2
(Me), 44.5 (NMe2), 61.2 (OCH2), 62.0 (OCH2), 114.2 (C),
127.3 (C), 128.5 (2CH), 129.4 (CH), 130.5 (2CH), 131.7
(C), 137.8 (C), 156.3 (C), 160.1 (C¼O), 165.2 (C¼O), 178.2
(C¼O) ppm.
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